The adrenal gland produces three kinds of steroid hormones: glucocorticoids, mineralocorticoids and adrenal androgens. Cortisol and corticosterone are the essential human glucocorticoids which play important roles in salt and water homeostasis and blood pressure control. Clinical conditions arising from an excess or deficiency of glucocorticoids or mineralocorticoids include Cushing's syndrome, primary aldosteronism, Addison's disease and congenital adrenal hyperplasia (Shimojo and Stewart, J. Endocrinol. Invest., 1995, 18, 518-532).
Obesity is associated with adverse metabolic consequences such as diabetes and dyslipidemia. One identified cause of viceral obesity and metabolic complications is exposure to excessive levels of glucocorticoids (Bjorntorp and Rosmond, Nutrition, 2000, 16, 924-936).
The enzyme hydroxysteroid 11-beta dehydrogenase 1 (also known as HSD11B1, HSD-11 and 11-beta-OHSD) plays a pivotal role in determining intracellular glucocorticoid concentrations by regenerating active glucocorticoid (cortisol in humans, corticosterone in rats and mice) from inactive cortisone and 11-dehydrocorticosterone and has been suggested to serve as a tissue-specific amplifier of glucocorticoid action (Bjorntorp and Rosmond, Nutrition, 2000, 16, 924-936).
Hydroxysteroid 1′-beta dehydrogenase 1 has been cloned and mapped to chromosome 1q32-q34 (Tannin et al., J. Biol. Chem., 1991, 266, 16653-16658). It is widely expressed, most notably in liver, lung, adipose tissue, vasculature, ovary and the central nervous system (Seckl and Walker, Endocrinology, 2001, 142, 1371-1376).
Rask et al. have recently demonstrated elevated levels of hydroxysteroid 11-beta dehydrogenase 1 activity in adipose tissue from obese humans and impaired activity in the liver (Rask et al., J. Clin. Endocrinol. Metab., 2001, 86, 1418-1421).
Masuzaki et al. have created transgenic mice which overexpress hydroxysteroid 11-beta dehydrogenase 1 selectively in adipose tissue to an extent similar to that found in adipose tissue of obese humans. These mice had increased adipose levels of corticosterone and developed visceral obesity that was exaggerated by a high-fat diet. The mice also exhibited pronounced insulin-resistant diabetes and hyperlipidemia, leading to a proposal that increased adipocyte hydroxysteroid 11-beta dehydrogenase 1 activity may be a common molecular etiology for visceral obesity (Masuzaki et al., Science, 2001, 294, 2166-2170).
Mice homozygous for a targeted deletion of hydroxysteroid 11-beta dehydrogenase 1 gene are viable and developmentally normal but cannot regenerate active corticosterone from inert 11-dehydrocorticosterone in vivo, demonstrating that hydroxysteroid 11-beta dehydrogenase 1 is the sole 11-beta-reductase in the body (Kotelevtsev et al., Proc. Natl. Acad. Sci. U.S. A., 1997, 94, 14924-14929). The hydroxysteroid 11-beta dehydrogenase 1-deficient mice show attenuated activation of glucocorticoid-sensitive hepatic gluconeogenic enzymes in response to stress or high-fat diets and have a disease resistant phenotype (Kotelevtsev et al., Proc. Natl. Acad. Sci. U.S.A., 1997, 94, 14924-14929).
The thiazolidinedione (TZD) class of antidiabetic agents that are ligands for peroxisome proliferator-activated receptor-gamma have been shown to reduce adipocyte hydroxysteroid 11-beta dehydrogenase 1 mRNA and activity both in vivo and in vitro. Because TZDs preferentially reduce visceral fat accumulation in humans, suppression of adipose hydroxysteroid 11-beta dehydrogenase 1 by TZDs could be a mechanism for this fat redistribution and may play a role in their antidiabetic effects (Berger et al., J. Biol. Chem., 2001, 276, 12629-12635).
These findings strongly suggest that increased adipocyte hydroxysteroid 11-beta dehydrogenase 1 is a common molecular mechanism for visceral obesity and diabetes and may be an appropriate pharmaceutical target for the treatment of these disorders.
In addition to the TZD class of antidiabetic agents discussed above, other known small molecule inhibitors of hydroxysteroid 11-beta dehydrogenase 1 include glycyrrhetinic acid and carbenoxolone (MacKenzie et al., J. Clin. Endocrinol. Metab., 1990, 70, 1637-1643; Stewart et al., Clin. Sci., 1990, 78, 49-54).
Disclosed and claimed in PCT publication WO 01/90093 is the use of 2-aminothiazole-derivatives as inhibitors of hydroxysteroid 11-beta dehydrogenase 1 in the manufacture of medicaments for the prevention, management or treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperinsulinemia, osteoporosis, tuberculosis, depression, virus diseases and inflammatory disorders (Nilsson, 2001).
Disclosed and claimed in PCT publication WO 01/30383 is a medicament comprising hydroxysteroid 11-beta dehydrogenase 1 antisense oligonucleotides combined with an antigen in order to improve and optimize tolerance induction (Wilckens, 2001).
Antisense phosphorothioate oligonucleotides targeting the start codon of human hydroxysteroid 11-beta dehydrogenase 1 have been employed in investigations of hydroxysteroid 11-beta dehydrogenase 1 activity and effects on vascular contractile response and glucocorticoid metabolism in human vascular tissue (Hatakeyama et al., Front. Sci. Ser., 2000, 29, 173-174; Souness et al., Steroids, 2002, 67, 195-201). Currently, there are no known therapeutic agents that effectively inhibit the synthesis of hydroxysteroid 11-beta dehydrogenase 1. To date, investigative strategies aimed at modulating hydroxysteroid 11-beta dehydrogenase 1 expression have involved the use of small molecule inhibitors, gene knock-outs in mice and antisense oligonucleotides. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting hydroxysteroid 11-beta dehydrogenase 1 function.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of expression of hydroxysteroid 11-beta dehydrogenase 1.
The present invention provides compositions and methods for modulating expression of hydroxysteroid 11-beta dehydrogenase 1.